Department of Molecular and Biomedical Pharmacology and the Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536-0230, USA.
J Alzheimers Dis. 2010;20(2):637-46. doi: 10.3233/JAD-2010-1397.
The study of Alzheimer's disease (AD) pathogenesis requires the use of animal models that develop some amount of amyloid pathology in the brain. Aged canines (beagles) naturally accumulate human-type amyloid-beta peptide (Abeta) and develop parallel declines in cognitive function. However, the type and quantity of biochemically extracted Abeta in brain and cerebrospinal fluid (CSF), its link to aging, and similarity to human aging has not been examined systematically. Thirty beagles, aged 4.5-15.7 years, were studied. Abeta40 and Abeta42 were measured in CSF by ELISA, and from SDS and formic acid extracted prefrontal cortex. A sample of the contralateral hemisphere, used to assess immunohistochemical amyloid load, was used for comparison. In the brain, increases in Abeta42 were detected at a younger age, prior to increases in Abeta40, and were correlated with an increased amyloid load. In the CSF, Abeta42 decreased with age while Abeta40 levels remained constant. The CSF Abeta42/40 ratio was also a good predictor of the amount of Abeta in the brain. The amount of soluble oligomers in CSF was inversely related to brain extractable Abeta, whereas oligomers in the brain were correlated with SDS soluble Abeta42. These findings indicate that the Abeta in the brain of the aged canine exhibits patterns that mirror Abeta deposited in the human brain. These parallels support the idea that the aged canine is a useful intermediate between transgenic mice and humans for studying the development of amyloid pathology and is a potentially useful model for the refinement of therapeutic interventions.
阿尔茨海默病（AD）发病机制的研究需要使用在大脑中产生一定量淀粉样蛋白病理学的动物模型。老年犬（比格犬）自然会积累人类类型的淀粉样β肽（Abeta），并出现认知功能平行下降。然而，大脑和脑脊液（CSF）中生物化学提取的 Abeta 的类型和数量、其与衰老的关系以及与人类衰老的相似性尚未得到系统研究。研究了 30 只年龄在 4.5-15.7 岁的比格犬。通过 ELISA 测量 CSF 中的 Abeta40 和 Abeta42，并从 SDS 和甲酸提取的前额皮质中测量。用于评估免疫组织化学淀粉样蛋白负荷的对侧脑半球样本用于比较。在大脑中，Abeta42 的增加在 Abeta40 增加之前在更年轻的年龄被检测到，并且与淀粉样蛋白负荷的增加相关。在 CSF 中，Abeta42 随年龄下降，而 Abeta40 水平保持不变。CSF Abeta42/40 比值也是大脑中 Abeta 含量的良好预测指标。CSF 中可溶性寡聚物的量与脑可提取 Abeta 呈反比，而脑内寡聚物与 SDS 可溶性 Abeta42 相关。这些发现表明，老年犬大脑中的 Abeta 表现出与在人脑沉积的 Abeta 相匹配的模式。这些相似之处支持这样一种观点，即老年犬是研究淀粉样蛋白病理学发展的转基因小鼠和人类之间的有用中间物，并且是用于改进治疗干预措施的潜在有用模型。
